ISO pharma glass vial formats

Hello everyone – I often get asked to comment about current trends in pharmaceutical glass packaging.?While it’s perhaps not the most exciting topic out there, I view the continued growth in adoption of the standardized ISO vial formats as being critically important for pharma manufacturing. ?

The publication of the ISO standard formats for glass vials is by no means a recent thing.?The standards for vials made from tubular glass and molded glass were first published in 1989 and have been gradually revised over time.?ISO 8362-1:2018 and ISO 8362-4:2011 provide specifications for converted tubular and molded (also sometimes spelled moulded) glass vials, respectively (see Footnote 1).? I’m also often asked why tubular formats are called “R” vials and molded formats are called “H” vials.? The German Institute for Standardization (a.k.a. Deutsches Institut für Normung = DIN) was the leader in developing standards for pharmaceutical glass packaging.?The words “R?hrenglas” and “Hüttenglass” are the German words for “Tubular glass” and “Molded glass”, respectively.? The use of the letters “R” and “H” in the ISO standard formats are simply following designations originally developed by DIN.?Table 1 summarizes some of the key dimensions for both the R and H vial formats.? There’s a lot of information in Table 1, and so I just want to make a couple points for now.?

Both format types cover a seemingly broad range of fill volumes.?However, you’ll notice that tubular vials support the lowest nominal brimful capacity – this leads to another comment.?ISO 5H vials might have a standardized specification, but smaller capacity molded glass vials are less frequently used in practice.?Similarly, an ISO 100R vial exists on paper, but it’s much more common to use a molded vial for higher fill volumes.? I think Figure 1 reinforces this point – it shows the ratio of the allowable tolerance to the nominal brimful capacity as a function of brimful capacity for both ISO R and H vial formats.? For example, this ratio for a 2R vial is 0.5 mm (the tolerance) divided by 4 mm (the nominal brimful capacity) to give a value of 0.125.? I find it interesting that there appears to be three bands of behavior here: 1) the ratio for R vials is lower than H vials up to a brimful capacity of ~20 mL (i.e. it’s easier to make smaller vials from converted tubular glass), 2) the ratios are fairly similar for both formats between ~20 mL to ~40 mL, and 3) the trend then inverts with the ratio for R vials being higher than H vials for the largest fill volumes (i.e., it’s generally easier to make larger vials from molded glass).

You can also use these dimensions to make some inferences about relative performance within a series.? For example, Table 2 shows the ratios of vial height to vial outer diameter for R vials.? I’ve color coded the ratios to simplify interpretation.? The values in green and orange/red correspond to the lowest and highest ratio values, respectively, while the more yellow colors are within the middle of the range.? A low value to this ratio implies a more stable vial that is less prone to tipping over while being transported on a fill-finish line.? Also note the 4R vial that with a height to diameter ratio of 2.81, the highest value within the series.? The 4R vial is notorious for tipping over on lines.? It’s why I generally recommend users to stay away from this format, particularly for bulk filling lines.

There are numerous benefits to using standardized ISO vial formats for your drug product, including but not limited to:

·??????Supply chain security – the growth in ISO vial adoption means that suppliers are more likely to keep these standardized formats in inventory, thereby leading to shorter lead times.?Standardized vial formats also help stabilize supply by facilitating second sourcing.

·??????Component compatibility – the glass vial is just one part of a complete container-closure system.?Maintaining sterility of a drug product requires that the vial is compatible with the elastomeric stopper and aluminum seal (see Footnote 3).?Using standardized vial formats (in particular, the dimensions associated with the flange and neck interior) helps to ensure that primary packaging components from a variety of suppliers have a reasonable chance of working together.

·??????Design for manufacturing – standardized vial formats can reduce the number of (expensive) change parts that need to be kept in inventory for your fill-finish line.?This in turn can also reduce the complexity of job changes for a drug product portfolio that is based on a common vial size.?Of course, these statements can also be true if a pharma manufacturing site is consistently using a non-ISO vial format.?However, the explosive growth of contract drug development and manufacturing has made the adoption of ISO standard vial formats increasingly important.? Furthermore, the increasing adoption of automation in fill-finish manufacturing in combination with pre-washed, pre-sterilized packaging components (so-called “ready to use” or “ready to fill” packaging) is generally predicated on the use of ISO formats.

Finally, I should emphasize that Table 1 is just a summary of key dimensions taken from ISO 8362-1 and 8362-1 for converted tubular and molded vials, respectively.? There are other vial dimensions specified in these documents that do not follow the same pattern of a nominal dimension with a plus/minus tolerance.? The bottom concavity of a converted tubular vial is one example.? ISO 8362-1 states that the bottom concavity should be no more than 0.7 mm for 2R to 15R, no more than 1 mm for 20R to 30R, and no more than 1.5 mm for 50R and 100R.? There is no lower limit and no associated tolerance on bottom concavity.? Could I envision a scenario where variability in bottom concavity of a vial makes a difference?? Sure – operations such as lyophilization can be impacted by the bottom geometry of the vial.? ??There are other vial specifications such as shoulder radius and heel radius that are target values – e.g., the shoulder of a 2R vial should be approximately 2.5 mm according to ISO 8362-1.? Whether or not any of this is of practical importance to your process has to be evaluated on a case-by-case basis, ideally in collaboration with your packaging supplier.

Questions or comments??– please leave them in the comments or feel free to directly contact me.

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Footnotes

1. References:

a.?ISO 8362-1:2018, Injection containers and accessories — Part 1: Injection vials made of glass tubing, 4th Edition.

b.?ISO 8362-4:2011, Injection containers and accessories — Part 4: Injection vials made of moulded glass, 3rd Edition.

2. The nominal flange heights for tubular and molded vials appear to be different.?However, ISO 8362-4:2011 goes on to say that: “Owing to the differences in manufacturing procedures for injection vials made of glass tubing and those made of moulded glass, the measuring point at the brim is different in each case. It follows that the height measured from the lower edge of the flange to the measuring point at the brim of injection vials made of moulded glass is 0,2 mm more than that of injection vials made of glass tubing. But, in practice, the same aluminium caps may be used for both types of vial.”? This touches on a related topic that will be the subject of another post in the near future – the actual measurement of vial flange height is not entirely straightforward.

3.?There is of course the possibility of using a press-fit cap as well, although separate stoppers and seals are the most common approach at this time.?Either way, compatibility with the vial is still essential.